Jebanesan_2026_Biol.Psychiatry__

Monoacylglycerol lipase (MAGL) is the primary enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), a key regulator of endocannabinoid system tone, thereby influencing synaptic function and neuroinflammation. These processes are central to the neurobiology of substance use disorders (SUDs), yet the contribution of MAGL to addiction remains fragmented across studies. With growing interest in MAGL as a therapeutic and imaging target, a comprehensive synthesis is timely. This systematic review aimed to evaluate whether exposure to substances of abuse alters MAGL expression or activity, and whether manipulating MAGL function affects SUD-relevant outcomes. Following the PRISMA 2020 guidelines, we screened preclinical studies that assessed MAGL directly in the context of substance exposure. A total of 42 studies met the inclusion criteria. Chronic substance exposure led to modest, region-specific changes in MAGL protein expression. In the hippocampus, alcohol increased MAGL levels. In the striatum, levels were largely unchanged across substances. In the prefrontal cortex, changes were only seen after repeated stimulant exposure. Findings for opioids and ketamine were mixed and inconsistent across regions. MAGL inhibition consistently reduced withdrawal-like behaviors across cannabis, opioid, and nicotine models, but effects on reward-related behaviors were more variable - reducing opioid-related reward while showing less consistent effects in other models. Collectively, these findings from preclinical models of SUDs suggest a more robust role for MAGL in withdrawal-like-states than in reward. They highlight the need to better understand the dynamic endocannabinoid adaptations, including cannabinoid receptor function and 2-AG signaling, that shape addiction-related behaviors.